Arrestin is a central component of phototransduction, primarily functioning to inactivate the visual pigment in rod photoreceptors. The function of arrestin is apparently broader than just rhodopsin inactivation, however, because arrestin translocates dramatically in response to illumination conditions, moving almost completely to the inner segments of photoreceptors in the dark and to the outer segments in the light. Although this phenomenon of arrestin translocation has been known for more than twenty years, the function has remained elusive. Using tools recently developed, this proposed research will identify the specific function of arrestin translocation in the biology of photoreceptors. We hypothesize that arrestin translocation is a way that rod photoreceptors modulate the metabolic response of the cells to light, preventing rod metabolic decline that could lead to cell death and retinal degeneration under bright illumination conditions. Using model animals that express an arrestin specifically modified to retain its interaction with rhodopsin, but lack translocation, we will be able to assess the function of arrestin translocation through the following three specific aims. 1) Determining the effects on rod function of an arrestin that is defective in translocation. 2) Determining how the phospholipase C cascade initiates and regulates arrestin translocation. 3) Determining how arrestin modulates the metabolic supplies of the photoreceptor, focusing on the interaction between arrestin and enolase. Success in this research will not only provide an important understanding for some of the fundamental processes necessary to achieve vision and maintain a healthy retina, but will also identify important intervention points that could be used to delay retinal degeneration caused by a variety of genetic defects. PUBLIC HEALTH RELEVANCE: Arrestin is a protein at the heart of the visual process, aiding in the conversion of light to an electrical signal that can be interpreted by the brain. Surprisingly, arrestin moves in the photoreceptors in response to lighting conditions. The experiments contained in this proposal are designed to identify the role this movement of arrestin plays in the visual process, hypothesizing that translocation of arrestin is responsible for maintaining the metabolic reserves of the photoreceptors and preventing retinal degeneration.